The proposed clinical trial will assess the efficacy of and mechanisms of change activated by two treatment strategies designed to help people achieve permanent abstinence from tobacco. Basic research on drug motivation and learning suggests that altering associations among setting events, drug use, and the reinforcing consequences of use prior to a smoking cessation attempt may enhance success in quitting. Smoking remains the leading preventable cause of death among adults in the U.S.1 and relapse remains the most likely outcome of any smoking cessation attempt2. Although treatment advances have helped many people quit smoking, many more wish to quit but fail to do so despite repeated attempts2. The proposed project will use an experimental design to assess the efficacies of two treatment strategies designed to alter distinct learned associations between smoking and its antecedents and consequences. The first strategy involves graded exposure to aversive nicotine withdrawal symptoms through seven progressively longer periods of abstinence, or "practice quitting" sessions, followed by an aversive smoke holding procedure that will reduce the reinforcing effects of returning to smoking after each practice quitting session. The second strategy involves smoking denicotinized cigarettes for the first 6 weeks of a quit attempt in order to temporarily reduce withdrawal through associative effects and then extinguish the nicotine self-administration ritual. The proposed study comprises 3 treatment conditions. All subjects will receive a standard cessation treatment (ST) including a 6-weeks course transdermal nicotine patch therapy and individual smoking cessation counseling. The control condition will receive only this treatment. Subjects in the standard treatment plus Withdrawal Exposure + Smoke Holding (ST+WE/SH) condition will also receive graded withdrawal exposure and smoke holding pre-quit. Subjects in the final condition (ST+WE/SH+DC) will receive standard treatment, withdrawal exposure and smoke holding, and a 6-week supply of denicotinized cigarettes to smoke after quitting use of usual-brand cigarettes. We predict that ST+WE/SH will promote abstinence, relative to the ST condition, and that ST+WE/SH+DC will promote abstinence relative to ST+WE/SH. We predict that ST+WE/SH will primarily extinguish learned associations between smoking and its antecedents (e.g., withdrawal distress) whereas ST+WE/SH+DC will provided conditioned withdrawal relief in the early part of the quit attempt and will ultimately extinguish associations between smoking and its positive consequences. We will investigate these hypotheses using mediation analyses. The goal of this research is to identify new, learning-based treatment components that can be added to existing treatments to increase successful smoking cessation. PUBLIC HEALTH RELEVANCE: The proposed study will test two treatment strategies designed to help smokers quit smoking. The study will tell us whether combining distinct treatments enhances quitting rates and will identify changes that may account for treatment benefits. The project will test the efficacy of behavioral and pharmacological treatments designed to interrupt learned associations among triggers to smoke, smoking behavior, and the positive consequences of smoking.